Certain 1-aminomethyl-6-phenyl 4h-s-triazolo(4,3-a)(1,4)benzodiazepines

ABSTRACT

1-(3-((1,3-DI(O=)-ISOINDOLIN-2-YL)-CH2-),5-(X-CH2-)-4H-   1,2,4-TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-BENZENE(A)   WHEREIN A AND B HAVE THE SIGNIFICANCE OF ABOVE, AND WHEREIN X IS CHLORO OR BROMO; (5) TREATING B WITH AN AMINE OF THE FORMULA   R&#39;&#39;-NH-R&#34;   WHEREIN R&#39;&#39; IS ALALKYL DEFINED AS ABOVE, OR HYDROGEN, WHEREIN R&#34; IS ALKYL DEFINED AS ABOVE OR TOGETHER   R&#39;&#39;-NN-R&#34;   IS PYROLIDINO, PIPERIDINO, 4-METHYL- OR 4-PHENYLPIPERAZINO, IN THE PRESENCE OF AN ALKALI IODIDE, TO GIVE THE CORRESPONDING 2-(5-((SUBSTITUTED AMINO)METHYL) -3- (PHTHALIMIDOMETHYL)-4H-1,2,4TRAZOL-4-)BENZOPHENONE VI:   1-(3-((1,3-DI(O=)-ISOINDOLIN-2-YL)-CH2-),5-(R&#39;&#39;-N(-R&#34;)-   CH2-)-4H-1,2,4-TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-   BENZENE(A)   WHEREIN R&#39;&#39;, R&#34;, A AND B HAVE THE SIGNIFICANCE AS DEFINED ABOVE; AND (6) HEATING VI WITH HYDRAZINE HYDRATE TO GIVE THE COMPOUND OF FORMULA VII ABOVE.   WHEREIN A AND B HAVE THE SIGNIFICANCE OF ABOVE; (4) TREATING IV WITH A HALOGENATING AGENT SELECTED FROM THIONYL CHLORIDE AND PHOSPHORUS TRIBROMIDE TO OBTAIN THE CORRESPONDING 2-(3-(PHTHALIMINOMETHYL)5-(HALOMETHYL)-4H-1,2,4- TRIAZOL - 4 - YL)BENZOPHENONE OF FORMULA V:   4H-1,2,4-TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-BENZENE(A)   1-(3-((1,3-DI(O=)-ISOINDOLIN-2-YL)-CH2-),5-(HO-CH2-)-   1-(R&#34;-N(-R&#39;&#39;)-CH2-),6-(PHENYL(B)-)-4H-S-TRIAZOLO(4,3-A)   (1,4)BENZO(A)DIAZEPINE   WHEREIN A AND B HAVE THE SIGNIFICANCE OF ABOVE; (3) TREATING III WITH FORMALDEHYDE AT 100 TO 150*C. TO OBTAIN THE CORRESPONDING 2(3-(PHTHALIMIDOMETHYL)-5-(HYDROXYMETHYL)- 4H-1,2,4-TRAZOL-4-YL)BENZOPHENONE OF THE FORMULA IV;   TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-BENZENE(A)   1-(3-((1,3-DI(O=)-ISOINDOLIN-2-YL)-CH2-)-4H-1,2,4-   WHEREIN A AND B HAVE THE SIGNIFICANCE OF ABOVE; (2) TREATING II WITH PHTHALIMIDE, TRIPHENYLPHOSPHINE AND DIETHYL AZODICARBOXYLATE FOR 2-36 HOURS AT BETWEEN 0-40*C. TO OBTAIN THE CORRESPONDING 2-(3(PHTHALIMIDOMETHYL)-4H-1,2,4-TRIAZOL-4-YL)BENZOPHENONE OF FORMULA III   BENZENE(A)   1-(3-(HO-CH2-)-4H-1,2,4-TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-   WHEREIN A AND B HAVE THE SIGNIFICANCE OF ABOVE, WITH FORMALDEHYDE TO OBTAIN THE CORRESPONDING 2-(3-(HYDROXYMETHYL)-4H-1,2,4-TRIAZOL-4-YL)BENZOPHENONE OF FORMULA II   1-(4H-1,2,4-TRIAZOL-4-YL-),2-(PHENYL(B)-CO-)-BENZENE(A)   IS PYRROLIDINO, PIPERIDINO, MORPHOLINO, 4-METHYL- OR 4PHENYLPIPERAZINO; AND WHEREIN THE RINGS A AND B ARE UNSUBSTITUTED OR SUBSTITUTED BY ONE OR TWO SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKYL, ALKOXY, ALKYLTHIO, ALKYLSULFINYL, ALKYLSULFINYL, ALKANOYLAMINO IN WHICH THE CARBON MOIETY IS OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND DIALKYLAMINO IN WHICH THE ALKYL GROUP IS DEFINED AS ABOVE, WHICH COMPRISES THE STEPS: (1) HEATING TO A TEMPERATURE OF 100-150*C. A MIXTURE OF A 2-(4H-1,2,4:TRIAZOL-4-YL)BENZOPHENONE OF THE FORMULA I 1. A PROCESS FOR THE PRODUCTION OF 1(-(SUBSTITUTED AMINO)METHYL) -6- PHENYL-4H-S-TRIAZOLOR(4,3-A)(1,4)BENZODIAZEPINES OF FORMULA VII:   WHEREIN R&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, WHEREIN R&#34; IS ALKYL AS DEFINED ABOVE, OR, TOGETHER   R&#39;&#39;-N(-R&#34;)-

CERTAIN 1-AMINOMETHYL-6-PHENYL 4H-s- TRIAZOLO[4,3-a][1,41BENZODIAZEPINES N Martin Gall, Kalamazoo and Jackson B. Hester, Jr., OH OH Galesburg, Mich., assignors to The Upjohn, Comp ny, A 2- Kalamazoo, Mich. I H s t I No Drawing. Filed Feb. 14,1973, Ser. No.'332,293 p, 6

Int. Cl. C07d 57/02, 99/02 US. Cl. 260-247.1 11 Claims v ABSTRACT or DISCLOSURE A multi-s-tep process for. the preparation of l-[amino- (or 1,-substituted .amino)methyl]-6-phenyl-4H-s-triazo1o- [4,3 -a][1,4]benzodiazepines of the formula X By n v N-m-c N i RI! v, I A

wherein R and R" are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, or together RI r BACKGROUND-OF INVEN'fibN Field ofthe'inyention This invention-is directed to'a newpr ocess for organic compounds and is particularly concerned with a process for 1-[amino(or l-substituted amino)methyl1-6- pheny1-4H-s-tria'zolo[4,3-a][1,4]benzodiainepines;

The process of production therefor can be illustrative ly'representedasfollows:

I I E 0 A i T m- In: {I

VII wherein X is chloro or bromo; wherein R' is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R" is alkyl of 1 to 3 carbon atoms, inclusive, or, together /N RI! I is pyrrolidino, piperidino, morpholino, 4-methyl-, or 4- phenylpiperazino, andYwherein the rings A and B are unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, nitro, cyano, trifiuoromethyl, and alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino in which the carwherein the designation X, and B have the same sig- The process of this invention comprises:

1. treating a compound of formula I with formaldehyde at 100-150 C. to obtain the compound of formula II;

2. treating II w ith phthalimide, triphenylphosphine and diethyl azodiciarbokylate between2'3 6 I hour'sf a't O to 40 C.,to 6b int'hecorresponding' compoundof'formula II-I;

"tuig lIIwithiformaldehydeat 100 150 c. wobtaina compound of formula IV;" l 4; treating-:IV with a halogenating agent "selected [from thionyl chloride or phosphorus ltribromide' to obtain the product'V;

5. treating V with a primaryor secondary amine selected from..monoalk yl-. or,,dialkylamine,, pyrrolidine, piperidin, i-m'ethyland 4-pl1'enylpiperazine,"aud morpholineto obtain the corresponding compound. and 6:- treating- VI withhydrazine' to obtain 'the 'compound bon moiety is of 1 to 3 carbon atoms, inclusive, and dialkylamino in which the alkyl group is defined as above.

In the event that a l-unsubstituted amino compound is wanted (R"=R"=hydrogen), the method of synthesis has to be slightly modified. It can be illustratively shown as follows: ,3 3

N xcn \w I ENE,

VIII

If an unsubstituted amine is desired compound V is treated with ammonia 'to give compound VIII and VIII is treated with hydrazine to give 't'he'l-aminomethyl compound IX. "5'

The method thereforeturnishes compounds of the formulaX 5 wherein Rf and R" are selected from the group consisting of h'ydrog' alkyl'of 1' "to 3"carbon atoms, inclusive, or

is pyrrolidino, piperidino', *morpholino, 4-methyl-, or 4 phenylpiperazino; and ,wherein the-Tings A and B- are unsubstituted" or substitutedby, one or two --substituents selected from the group consisting-,- of halogen, I nitro, cyano, trifiuoromethyl, and alkyl, alkoxy, alkylthio, alkylsulfinyl, all ylsulfonyl,"'allianoylaminti in which the carbon moiety is of 1 to '3 carbon atoms, "inclusive; and dialkylamino in which the alkylmoiety is of .1 to 3 carbon atoms.

DESCRIPTION OF THEPREFERRED EMBODIMENT:

4. amino, and diisopropylaminm;

The alkanoylamino groups of lito 3 carbon atoms consists of formamido I -NH-f-c-n acetamido and propionamidoi The compounds of the formulae VII and IX including acid addition salts thereof have sedative, tran'quilizing and anti-depressant effects in mammals, including man and. birds.

Sedative effects of e.g. 8-chloro-l-[ (dimethylamino) methyl]-6-phenyl 7 4H s triazolo[4,3-a] [1,4]benzodiazepineare shown by the following tests in mice:

Chimney test [-Med. Exp. 4, 145- (1961)]: The effective intraperitoneal dosage for 50% of mice (ED;,.,) is 2.3 mg./kg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the eifective dosage, 5 of the mice failed doing it.

Dish test Pedestal test The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute. The ED (intraperitoneal administration) is 0.8 mg./kg.-

4 Nicotine antagonism test Mice inia of 6 are injected with the test com- I below.

pound, 8-chloro-1-[(dimethylamino)methyl] 6 phenyl- 4H-s-triazolo[4,3-a][1,4]benzodiazepine. Thirty minutes later the mice including control (untreated) mice are injected' with nicotine 'salicylate (2 mg./kg.). The'control mice show overstimulation, he, (1) running convulsions (2) tonic extensor fits; followed by (3) death. An intraperitoneal dosage of .11 mg./kg.of'the test compound protected 50% of the animals against'(3).

-Antagonism to strychnine (as sulfate) TABLE 1- V benzodlazepine 0.63 0.11 0.4 0.08

The novel compounds'of formula X and pharmacologically "acceptable acid addition salts and N-oxides thereof have antidepressant activity and are thus useful for the treatment of depression in mammals or birds.

The main function of an anti-depressant is to return the depressed individual to normal functioning. This should be carefully differentiated from psychic stimulants such as the amphetamines which produce overstimulation in the normal individual.

Many diiferent methods have been and are used to evaluate antidepressant activity. In general these methods involve antagonism to a depressant such as reserpine or tetrabenazine or a synergistic increase of the toxicity of certain compounds (i.e. yohimbine or 3,4-dihydroxy-' phenylalanine and comparison of the drug action of the new compound with other known antidepressants. No single test alone can determine whether or not a ne compound is an antidepressant or not, but the profile evidenced by various tests will establish the anti-depressant action if present. A number of such tests are described Hypothermic tests with oxotremorine: [1-(4-pyrroli dino-2-butynyl)2-pyrrolidinone] Oxotremorine (as well as apomorphineand tetrabena zine) produces hypothermic responses in mice. This response is blocked by anticholinergics and anti-depressants such as atropine and imipramine respectively.

Oxotremorine produces a very pronounced hypother- At a dose of 0.6 mg./kg. the body temperature of a mouse is decreased about 13 F. (when the mouse is kept at room temperature). This temperature decrease is an tagonized by anti-depressants e.g. desipramine, imipramine, doxepine, and others, as can be seen from Table II.

TABLE II Body temperature, F., change Absorpfrom vehicle controlaiter- Dose tron mgJkg time 15 30 60 90 1. (min.) mins. ns. mins. mins.

Oxotremorlne (control) O. 6 5. 8 11. 6 -13. 2 8. 0 Desipramine 25 30 3. 5 3. 5 4. 1 3. 6 Imipramine 25 30 0. 4 3. 3 5. 6 6. 4 Iprindole--. 25 30 6. 3 11. 8 12. 8 -11. 9 Doxepine. 25 30 2. 3 7. 1 -;11. 0 12. 3 Amitriptyh 25 30 +0. 7 2. 4 -=-5. 4 --6. 8 Amphetamine 5 30 1. 5 4. 3 4. 4 2. 2 Atropine. 3 30 +0. 6 0. 6 0. 7 0. 2

The present compounds were tested as follows. Four male mice of 18-22 g. (Strain CE=Carworth Farms) were injected intraperitoneally with 1 mg. of oxotremorine. The lowering of thebody temperature was measured rectally with an electronic thermometer, before and 30minutes after drug administration. After the drug ad ministrationthe mice were kept at '19" C. in cages. A four degree 'diiference between the control mice (oxotremorine alone) and the treated mice (oxotremorine and test compound) was used to indicate the antagonistic action ofthe test compound.

The test results are tabulated below: Y The ED is the dosage of the test compound at which half the mice had a temperature of at least 4' C. higher than the control mice.

H TABLE III p Compounds: I, I ED (mg/kg.) 8-chloro-1 [(dimethylamino)methyl] 6 phenyl 4H s triazolo[4,3] [2,4] benzo- Doxepine 14.9

- Potentiation of yohimbine aggregation toxicity: the LD of yohi-mbine hydrochloride in mice is 45 mg./kg. i.p. Administration of 30 mg./kg. of yohimbine hydrochloride was non-lethal. If an antidepressant is administered prior to the yohimbine hydrochloride (30 mg.) the lethality of the yohimbine hydrochloride is increased.

Ten male CF mice, 18-22 g., were injectedwith the anti-depressant and 30 minutes later with 30 mg. of yo himbine hydrochloride (YCl) in saline solution. After two hours, the LD are determined. No mice or only one mouse is killed by 30 mg. of (YCl). If (YCl) is administered in the presence of an anti-depressant anincrease of the toxicity of (YCl) is observed. The ED values of the new compound and standard medicament which causes 50% of the mice to die is shown in Table IV.

TABLE IV 5 g-/ [YCl] (30 mg.) control [YCl] and S-chloro 1 [dimethylamino)methyl]- 6-phenyl 4H s-triazolo[4,3-a] [1,4]benzodiazepine 12.5 [YCl] and 8 chloro 1 [(diethylamino)methyl]- 6 phenyl 4H s triazolo[4,3-a] [1,4]benzodiazepine 42 [YCl] and Iprindole [YOU and Imipramine 4.4 [YCl] Doxepine *':1'7.7

1 No deaths.

Potentiation 'of apomorphine gnawing TABLEV- Compound: ED (mg/kg.)

8 chloro 1 [(dimethylamino)methyl] --6- phenyl 4H-s-triazolo[4,3 a][l',4]'benz odi- ,7:

I azepine I a V 5.3 8 chloro 1 [(diethylamino)methyl],-6-phen yl 4H-s-triazolo[4,3 a][1,4] benzodiaze- 1 pine 14.9 Iprindole v I i Imipramine .17.7 Doxepine 17.7

;2;'-chloro-2 [3 (hydroxymethyl) -4H-1,2,4-triazol;

.The 1.11 :values in mice for. these compounds-are listed intable VI. v

Compound: LD (mg/kg.)

- 8 chloro 1 ['(dimethylamino)methyl]-'6- phenyl-4H s triazol o[4,3-a][1,4]benzodiazepine I.

8 chloro 1 [(diethylamino)methyl]-6- phenyl 4H s"- triazolo'[.4,3-a] [1,4]benzodiazepine Iprindole 450 Imipramine 178 Doxepin- I i 126 The ED and LD o f'the new compounds-compare thus favorably with standard "antidepressantcompounds on the market.

Other compounds of formula IV are anti-depressants as shown by table VII:

NoTn.YO=Yohimbine test, Oxo=0xotremorine test, Ap=Apomorphinetest. v

The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral, and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspension, sterile injectable forms, suppositories, bou'gies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins; lipids, calcium" phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Water or oils, e.g.,,coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the .active drug-sweetening coloring, and flavoring; agents maybeadded. For mammals .and birds, .food premixes with starch, oatmeal, dried fishmeat, fishmeal,flour,-.andthelike can be prepared.

As tranquilizers the compounds of formula X can be used in dosages of 0.02 mg. to 1 mg./kg."in oral or injectable preparations, as described above, to alleviate tension and anxiety in mammals, or birds, such as-e.g., occurs when animals" are in travel. I Other acid addition salts of the compounds" of formulae II, III, and IV' canbe made such as the'fluosilic'ic acid addition salts which are-useful mothproofing compounds or the trichloroacetates useful as herbicides against Johnson-grass, Bermuda grass, yellow foxtail,'and"green foxtail, and quacktgrass. The startingcompounds ofthis invention can'be produced according to the process described by Derieg et al., J. Heterocyclic Chemistry 8, 1-81 (1971): or..according to the processes shown in US. Pat. 3,709,898, issued Jan. 9, 1973.

Starting compounds, thus obtained, include 3,5-dicyano-2'-chloro-2-[3 (hydroxymethyl)-4H-l,2,4-

2',4'-diniethyl-2'-bromo-2- 3- (hydroxymethyl) -4H- triazol- 4-yl]benzophenone;

' triazol- 4-yl]benzophenone;'

6-methylsulfonyl-4-nitro-2- 3- (hydroxymethyl) -4H 1,2,4-tria2ol-4-yl]benzophenone; V

4-ethylsulfinyl-4-propyl-2-[3-(hydroxymethyl)-4H- 1,2,4-triazol-4-yl]benzophenone;

3-diethylamino-3-isopropyl-2- 3- (hydroxymethyl) -4H- 1,2,4-triazol-4-yl] benzophenone.

4'-acetamido-5-propoxy-2- [3- (hydroxymethyl) -4H- l,2,4-triazol-4-yl] benzophenone;

4-ethyl-4-nitro-2- [3- (hydroxymethyl) -4H- 1 ,2,4-triazoland the like. M

I In carrying out the process of this invention comprises treatingaselected 2-triazolobenzophenone compound I with formaldehyde at between IOU-150 C. for 3-18 hours. The formaldehyde used can either be in an aqueous solution, requiring" then a sealed vessel, or can be paraformaldeh yde in a high-boiling solvent e.g. toluene, xyle'nes, ethylbenzene, and the like. The product II, a 2- [3-(hydroxymethyl)-4H-1,2,4-triazol 4 yljbenzophenone is recovered and purified by conventional means, such as chromatography and crystallization.

Compound II in an inert organic solvent e.g. tetrahydrofuran is then treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate for 2-36 hours at a temperature of to 40 C..The resulting product IIIis obtainedby concentrating the reaction solution, extraction, chromatography and the like. J Compound H1 is then treated with formaldehyde or paraformaldehyde as described in the reaction with compound I, to give the corresponding 2-[5-(hydroxymethyl) 3- (phthalimidomethyl)-4H-l,2,4-triazol-4 yl] benzophenone'IV. v r

Compound IV is convertedto the halomethyl derivative with e.g. thionyl chloride or phosphorus tribromide. The chloro compound IV can,'moreover, be converted to the iodo compound in the usual manner i.e. treating the 'chlorocompound' withsodium iodide in acetone at 25- 56 for 6-8 hours. If thionyl chloride isused, no solvent is required, but if phosphorus tribromide is used, a solvent such as benzene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, and the like is usually employed. The reaction with thionyl chloride is preferably performed between 50-79 'C. during 1-3 hours, whereas the reaction with phosphorus tribromide is performed at 0-25" C. for 1 to 6 hours. The produetV a 2[5- (halomethyl) r '3 (phthalimidomethyl)-4H-l,2,4 triazol-4-yl]benzophenone, is recovered and purified by conventional procedures e.g. extraction, chromatography, crystallization, or the like. V p v The halogenated compounds V are then treated'with a primarylor secondary amine, e.g. methylamine, ethylamine, dipropylarnine, dimethylamine, diethylamine, ora cyclic amine such as pyrrolidine, piperidine morpholine, or 4-methylor 4-phenylpiperazine at temperatures be: tween 0-40,' in solvents such, as dioxane, ether, tetrahydrofur'an, methylene chloride, chloroform, and the like. The reaction is aided by the addition of sodium or potassium iodide. In the preferredembodiment of this invention the reaction iscarried out at low temperatures, e.g. 0 to C. for'5 to minutes, and thereafter the reaction mixture is allowed to warm up to room tem peratures and kept at this temperature for a period of 2 to 24 hours. The product, VI, isrecovered and purified, by standard procedures for exampleextraction, evaporation, chromatography, crystallization or the like.

10 Compound VI is then warmed with hydrazine in a lower alkanol e.g. methanol, ethanol, l-propanol, or 2-propanol to give the compound VII. The compounds VII are re covered and purified by conventional methods e.g. extraction, chromatography, crystallization or the like.

If an unsubstituted compound as of formula ]X is desired the compound of formula V is treated with ammonia to give compound VIII and VIII is treated with hydrazine to give compound IX.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. 3

EXAMPLE 1 5-Chloro-2-[3-(hydroxymethyl) -4H-l,2,4-

triazol-4-yl] benzophenone A stirred mixture of 5-chlor0-2-(4H-1,2,4-triazol-4-yl) benzophenone [M. E. Derieg, R. I. Fryer and S. S. Hillery, J. Heterocyclic Chem. 8, 181 (1971)] (0.01 mole), paraformaldehyde (0.33 g.) and xylene ('100 ml.) was warmed under nitrogen, in a bath maintained at 125 C. for 7 hours. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel g.) with 3% methanol-97% chloroform,. The product thus obtained was crystallized from ethanol-ethyl acetate to give 5 chloro 2 [3 (hydroxymethyl) 4H 1,2,4 -triazol- 4-yl]benzophenone.

EXAMPLE 2 5-Chloro-2- [3- (phthalimidomethyl) -4H- 1 ,2,4-triazol-4-yl1benzophenone EXAMPLE 3 S-Chloro-Z- [3- (phth alimidomethyl -4H-1,2,4- triazol-4-yl1benzophenone A solution of 1.00 mmol. of 5-chloro2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 5.0 ml. of methylene chloride was cooled to 0 in an ice bath. Triethylamine (0.150 g., 1.5 mmol.) was added and the solution was stirred for 5 minutes at 0. Cautiously, and drop wise over 4 min., 0.106 ml. (1.3 mmol.) of methanesulfonyl chloride was added and the solution was stirred for 20 minutes. The reaction was quenched on ice and extracted with a saturated aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated in vacuo. The resulting oil, dissolved in 4.0 ml. of freshly distilled tetrahydrofuran was treated at 0 with 0.332 g. (2.0 mmol.) of potassium iodide followed by 0.37 g. (2.0 mmol.) of potassium phthalimide. The mixture was stirred at 0 for 10 minutes then warmed to room temperature and stirred overnight. The mixture was quenched in an aqueous 5% sodium hydroxide solution and the product was extracted with chloroform. The chloroform layer was dried (sodium sulfate) and concentrated in vacuo to yield 5 chloro 2 [3 (phthalimidomethyl) 4H 1,2,4 triazol-4-yl1benzophenone.

11 EXAMPLEA 'S-Chloro-Z- ['5- (hydroxymethyl)-3- (phthalimido- R methyl) 4H: 1,2,4-triazol-4-yl] benzophenone EXAMPLE 5-Chloro-2-[5'-(chloromethyl)-3-(plith'alimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone A Solution of 5 chloro 2 [5 (hydroxymethyl) 3- (phthalimidomethyl) 4H 1,2,4 triazol 4 yl] benzophenone (0.001 mole) in thionyl chloride (2 ml.) was warmed during 40 minutes to a bath temperature of 78 C. and kept at 78-'-83 C. for 1 hour 25 minutes. It was then cooled and poured into ice water. This mixture was neutralized with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate- Skellysolve B hexanes to give 5-chloro-2-[S-chloromethyl) 3 (phthalimidomethyl) 4H 1,2,4 triazol 4 yl] benzophenone.

EXAMPLE 6 5-Chloro-2- 5- (bromomethyl) -3- (phthalimidomethyl) 4H- 1,2,4-triazo1-4-yl] benzophenone A solution of 5 chloro 2 [5 (hydroxymethyl) 3- (phthalimidomethyl) 4H 1,2,4 triazol 4 yl]benzophenone (0.001 mole) in dry, hydrocarbon-stabilized chloroform (5 ml.) was cooled in an ice bath and treated with phosphorus tribromide (0.1 ml.). The colorless solution was kept in the ice bath for 55 minutes and at ambient temperature (2224 C.) for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate and this mixturewas extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfateand concentrated. The residue was crystallized from methylene chloride-ethyl acetate to .give 5-chloro-2-[5-(bromomethyl)-3-(phthalimidomethyl) 4H-1,2,4-triazol-4-yl] benzophenone.

EXAMPLE 7 5-Chloro-2- [3- (iodomethyl) -5-(phthalimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone 5 Chloro 2 [3 (chloromethyl) s (phthalimidomethyl-4H-1,2,4-triazol-4-yl] benzophenone (0.001 mole) was added to a stirred solution of sodium iodide (300 mg.,

0.002 mole) in acetone, and the resulting mixture was stirred at ambient temperature for 7 hours and poured into ice water. This mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give 5-chloro-2-[3-(iodomethyl)- 5 (phthalimidomethyl) 4H 1,2,4 triazol 4 l] benzophenone. a V 7 EXAMPLE 8 5-Chloro-2[5-(dimethylamino)methyl-3-(phthalimidomethyl)-4H-1,2,4triazol-4-yl]benzophenone v A stirred suspension of 5-chloro-2-[5-(chloromethyl)- 3 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]'benzophe- 12 none hydrochloride. (0.01 mole) in tetrahydrofuran; 150 ml.) was cooled in an ice bathand treated with. sodium iodide (0.01 mole) and .125 ;ml. ofa solutionoftlimethylamine in methanolf Themixture wasf removed from the icebath, stirred aLambient temperature.for 1 8 hours and concentrated in vacuo. The residue'was mixed with water and extracted with methylene chloride. Thefextract was washed with brine, dried. over anhydrous potassium carbonateand concentrated. Crystallization of the residue from ethyl acetate gajve S-ehloro-Z-[S-(dimethylamiho) methyl] 3-(phthalimidomethyl)-4H-1,2,4-triazolyl-4-yl] benzophenone. 3

8-Chloro-1-(phthalimidomethyl)-6-phenyl-4H-sa I triazolo[4,3-a[1,4]benzodiazepine A stirred suspension. of 5-chloro-2-[3-(bromornethyl)- 5 (phthalimidomethyl) -,4H 1,2,4 triazol-4-yl]b en.zophenone (0.001 mole) in tetrahydrofuran (15-ml.).was cooled-in an ice. bath and treated with, a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution was allowedto warm. to-ambient temperatureand stand for 24. hours. It was then concentrated in vacuo. The residue was suspended in water, treated withalittle sodium bicarbonate and extracted with methylene ;chlo ride. The extract was washed with brine, dried with-anhydrouspotassium carbonate'and concentrated. The residue was crystallized fromethyl acetate to give 8-chloro- 1 r (phthalimidomethyl) 6-phenyl-4H- s-tria-zolo[4,3-a] [l,4]benzodiazepine.

EXAMPLE 1.1

8-Chloro-1-(aminomethyl)-6-phenyl-4H-s-triazolo- A stirred mixture of 8-chloro-I-( hthaIimid methyD- -6-pheriyl-4H-s-triazolo [4,3-a] [1',4-]benzodiazepine (0.5 62 mmole) and absolute'ethanol (3 ml.) was treated with hydrazine hydrate (0.05 ml., 1.04 mmole) 'anc l'lrefluxed for 2 hr. The cooled mixture was mixed with "water and extracted with chloroform. The extract was washed with water, dried with anhydrous sodium carbonate'and' concentrated. The residue" was chromatographed on" silica gel ('42 g.) with 5% methanol-% chlo'roformfThe product thus obtained was crystallized from methylene chloride-ethyl acetate to give 8"-c hlo'ro-l-(aminomethyl)- 6 phenyl 4H-s-triazolo[4,3-a] ['ll,4]benzodiazepine ,of melting point 1675-1725 C. 1 1

In a'varian't of this process a compound of formula'I istreated'an'd" warmed at -150 'Cfto give "1 2-'[3,$- bis(hydroxymeth'yl)' 4H- 1,2,4-triazol 4 yl]benzophenoiie (XI). Compound XI is then treated with phthalimide, triphenylphosphine and diet h'yl azodicarboxylate 'in an inert solvent such "as "tetrahy'drofuran to give 1,2- 3,5-bis (phthalimidomethyl)" 4H-1,2,4 triazol-4 yl'] benzophenone (VII) which warmed with hydrazine in an 1- or"2}all anol 13 of l to 3 carbon atoms such as methanol, ethanol or 1- or 2-propan0l to give a compound of formula IX.

8-Chloro-1-( aminomethyl)-6-phenyl-4H-s-triazolo [4,3-a] [l,4]benzodiazepine L A stirred mixture of -chlo'ro-2-(4H-l,2,4-triazol-4-yl) benzophenone (0.01 mole), paraformaldehyde (3 g.) and xylene 100ml.) was warmed, under nitrogen, in an oil bath maintained at 125 'C. for 7 hours. Themixture was then concentrated in vacuo. The residue was chromatographed on.si lica gel 150 g.,) with 3% methanol-97% I chloroform. The product thus obtained was crystallized from ethanol-ethyl acetate to give 5-ch1oro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone. I

A stirred mixture of 5-chloro-2-[3,5 bis(hydroxymeth yl) 4H 1,2,4-triazol-4-yl]benzophenone (0.002 mole), phthalimide (0.648 g., 0.0044 mole), triphenylphosphine (1.152 g., 0.0044 mole) and dry tetrahydrofuran (20 ml.), under nitrogen, was treated with diethyl azodicarboxylate (0.766 g., 0.0044 mole) was stirred at ambient'temperature for 23 hours. It was concentrated in vacuo and the residue was chromatographed on silica gel (75 g.) with 1.5% methanol-98.5% chloroform; 10 ml. fractions were collected. The product was crystallized from methanol-ethyl acetate to give 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.

A stirred mixture of 5-ch1oro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (0.5 mmole) and absolute ethanol (3 ml.) was treated with hydrazine hydrate (0.1 mol.) and refluxed for 2 hours. The cooled mixture was mixed with water and extracted with chloroform. The extract was washed with water, dried with anhydrous sodium carbonate and concentrated. The residue was chromatographed on silica gel (42 g.) with 5% methanol-% chloroform. The product thus obtained was crystallized from methylene chloride-ethyl acetate to give 8-chloro-1- (aminomethyl -6-phenyl-4H-s-triazolo [4,3 -a] [1,41benzodiazepine of melting point 167.5-172.5 C.

EXAMPLE 13 2',5 -Dich1oro-2- 3- (hydroxymethyl) -4H-1,2,4-triazol- 4-y1]benzophenone EXAMPLE 14 V 2',5-dichloro-2- [3 (phthalimidomethyl) 4H-1,2,4-

triazol-4-yl]benzophenone In the manner given in Example 2, a mixture of 2',5- dichloro 2 [3-(hydroxymethyl)-4H-1,2,4-triazol-4-yl] benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was reacted with diethyl azodicarboxylate to give 2',5-dichloro-2-[3-(phtha1imidomethyl) 4H 1,2, 4-triazo1-4-yl]benzophenone.

. EXAMPLE 15 2,5-Dichloro-2-[S-(hydroxymethyl) 3 (phthalimido- 3 methyl)-4H-1,2,4-triazol-4-y1)benzophenone In the manner given in Example 4, 2',5-dichloro-2-[3- (phthalimidomethyl) 4H 1,2,4-triazol-4-yl]benzophenone and paraformaldehyde were heated in xylene to give 2',5-dichloro 2 [S-(hydroxymethyl) 3 (phthalimidomethyl)-4H-1,2,'4-triazol-4-yl)benzophenone.

EXAMPLE 16 2,5-Dichloro-2- [5- chloromethyl -3- (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner given in Example 5, 2',5-dichloro-2-[5- hydroxymethyl) 3 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone was allowed to react with excess thionyl chloride to give 2,5-dichloro-2-[S-(chloromethyl) 3 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl1benzophenone.

EXAMPLE 17 2, 5 Dichloro-2- [5- (dimethylamino) methyl-3 phth alimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner given in Example 8, a suspension of 2',5- dichloro[5 (chloromethyl) 3 (phthalimidomethyl)- 4H 1,2,4 triazol-4-yl]benzophenone in tetrahydrofuran was treated with dimethylamine and then sodium iodide to give 2',5 dichloro 2- [5 (dimethylamino)methyl-3- (phthalimidomethyl) 4H 1,2,4 triazol 4-yl1benzophenone.

EXAMPLE 18 8-Chloro-1-[(dimethy1amino)methyl]-6-(o-chlorophenyl) -4I-I-s-triazo1o [4,3-a] 1,4]benzodiazepine In the manner given in Example 9, 2,5-dichloro-2- [5-[(dimethylamino)methyl] 3 (phthalimidomethyl)- I 7 I EXAMPLE 33 S-Methylthio 6 fluoro-4-ethylsulfonyl-2-[5 (hydroxymethyl) 3 (phthalimidomethyl) 4H 1,2,4 triazol- 4-yl]'benzophenone In the manner given in Example 4, -methylthio-6- fluoro 4' ethylsulfonyl 2 [3-(phthalimidomethyl)- 4H 1,2,4 triazol-4-yl]benzopheuone and paraformaldehyde were heated in xylene to give 5-methylthio-6-fluoro- 4'-ethylsulfonyl-2-[5-(hydroxymethyl) 3 (phthalimidomethyl)-4H-l,2,4-triazol-4-y1]benzophenone.

EXAMPLE 34 S-Methylthio 6 fluoro 4 ethylsulfonyl-Z-[S- (chloromethyl) 3 (phthalimidomethyl) 4H 1,2,4 triazol- 4-yl]benzophenone In the manner given in Example 5, 5-methylthio-6- fluoro 4' ethylsulfonyl 2 [5 (hydroxymethyl)-3- (phthalimidomethyl) 4H 1,2,4 triazol-4-yl1benzophenone was allowed to react with excess thionyl chloride to give 5 methylthio-6-fluoro-4'-ethylsulfonyl-2-[5-(chloromethyl) 3 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl] benzophenone.

EXAMPLE 35 5 Methylthio 6 fluoro 4' ethylsulfonyl 2 [5-pyrrolidinomethyl) 3 (phthalimidomethyl) 4H 1,2,4- triazo1-4-yl1benzophenone In the manner given in Example 8, a suspension of 5- methylthio 6 fluoro-4'-ethylsulfonyl-[5-(chloromethyl)- 3-(phthalimidomethyl) 4H 1,2,4triazol 4 yl]benzophenone in tetrahydrofuran was treated with pyrrolidine and then sodium iodide to give 5-methylthio-6-fluoro-4' ethylsulfonyl-Z-[S- (pyrrolidinomethyl) 3 (phthalimidomethyl) -4H-1 ,2,4-triazol-4-yl] benzophenone.

EXAMPLE 36 EXAMPLE 37 5-Chloro-2- [5-(piperidinomethyl)-3-(phthalimidomethyl) 4H-l,2,4-triazol-4-yl]benzophenone In the manner given in Example 8, a suspension of 5- chloro 2 [5-(chloromethyl) 3 (phthalimidomethyl)- 4H 1,2,4 triazol-4-y1]-benzophenone in tetrahydrofuran was treated with piperidine and then sodium iodide to give 5 chloro 2 [5-(piperidinon1ethyl) 3 (phthalimido)- methyl-4H-l,2,4-triazolee4-yl]benzophenone.

EXAMPLE 38 8-Chloro-1(piperidinomethyl)-6-phenyl-4H-s-triazolo- [4,3-a] [1,4] benzodiazepine In the manner given in Example 9, 5-chloro-2-[5- (piperidinomethyl) 3 (phthalimidomethyl)-4H-l,2,4triazo1- 4-yl]'benzophenone was refluxed in methanol with hydrazine hydrate to give 8 chloro 1 (piperidinomethyl)-6- pheny1-4H-s-triazolo [4,3-a [1,4]benzodiazepine.

EXAMPLE 39 2',5-Dichloro-2- [S-(morpholinomethyl) -3- (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner given in Example 8, a suspension of 2',5- dichloro 2 [5-(chloromethyl)-3-(phthalimidomethyl)- 4H 1,2,4 triazol-4-yl1benzophenone in tetrahydrofuran was treated with morpholine and then sodium iodide to give 2,5-dichloro 2 [5-(morpholinomethyl)-3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.

EXAMPLE 40 8-Chloro-l-(morpholinomethyl)-6-(o-chlorophenyl) 4H-s-triazolo[4,3-a][l,4]benzodiazepine In the manner given in Example 9, 2',5-dichloro-2-[5,- (moripholinomethyl) 3 (phthalimidomethyl)-4H-l,2,4- triazol-4-yl] benzophenone was refluxed in l-propanol with hydrazine hydrate to give 8-chloro-1-(morpholinomethyl)- 6-(o-chlorophenyl) 4H s triazolo[4,3-a] [l,4]benzodiazepine.

EXAMPLE 41 2,5 Dichloro 2 [5 [(4-methylpiperazino)methyl1-3- (phthalimidomethyl) 4H 1,2,4 triazol-4-yl1benzophenone In the manner given in Example 8, a suspension of 2',5- dichloro-Z [5- (chloromethyl) 3 (phthalimidomethyl)- 4H-l,2,4-triazol 4 yl]benzophenone in tetrahydrofuran was treated with 4methylpiperazine and then sodium iodide to give 2',5-dichloro-2 [5 [(4-methylpiperazino) methyl]-3-(phthalimidomethyl) 4H 1,2,4 triazol-4-yl] benzophenone.

EXAMPLE 42 8-Chloro-1- (4methylpiperazino) methyl] -6-(o-ch1orophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepine In the manner given in Example 9, 2',5-dihcoloro-2-[5- (4-methylpiperazino)methyl] 3 (phthalimidornethyl)- 4H-1,2,4-triazol-4-yl]benzophenone was refluxed in methanol with hydrazine hydrate to give 8-chloro-1-[(4-methylpiperazino)methyl]-6-(o-chloropheny1) 4H s triazolo- [4,3-a] [l,4]benzodiazepine.

EXAMPLE 43 S-Chloro-Z- [5-[ (methylamino)methyl]-3- (phthalimidomethyl) -4H- 1,2,4-triazol-4-yl] benzophenone In the manner given in Example 8, a suspension of 5 chloro-2-[5-(chloromethyl)-3-(phthalimidomethyl)- 4H-1,2,4-triazol-4 yl]benzophenone in tetrahydrofuran was treated with a solution of methylamine in ether and then sodium iodide to give 5-chloro-2-[S-(methylamino) methyl]-3-(phthalimidomethy1)-4H-1,2,4 triazo1 4 yl] benzophenone.

EXAMPLE 44 8-Chloro-1-[(methylamino)methyl]-6-phenyl- 4H-s-triazolo [4,3-a] 1,4] benzodiazepine In the manner given in Example 9, S-chloro-Z-[S-(methylamino)rnethyl] 3 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone was refluxed in methanol with hydrazine hydrate to give 8-chloro-1-[(methylamino) methyl]-6-phenyl 4H s triazolo[4,3-a][1,41benzodiazepme.

The phthalimido compound HI can also be prepared from the corresponding 3-amino-3,4-dihydro-4-hydroxy- 4-phenylquinazoline, as shown in Example 45.

EXAMPLE 45 5-Chloro-2-[3-(phthalimidomethyl)-4H- 1,2,4-triazol-4-yl]benzophenone A stirred mixture of phthaloylglycine (4.52 g., 0.022 mole) and dry tetrahydrofuran ml.) was cooled in an ice bath under nitrogen and treated with 3.56 g. (0.022 mole) of carbonyldiimidazole. The mixture was allowed to warm to ambient temperature and stand for 1.5 hours. It was then cooled in an ice bath and treated with 3- amino-6-chloro-3,4 dihydro 4 hydroxy-4-phenylquinazoline (2.74 g., 0.01 mole) [M. E. Derieg et al., Tetrahedron Letters, 3869 (1970)]. The resulting mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was mixed with water, treated with a little sodium bicarbonate and extracted with chloroform. The extract was washed with Water, dried over anhydrous sodium sulfate and concentrated. The crude residue was mixed with acetic acid (40 mL), refluxed under nitrogen for 1 hour and concentrated in vacuo. The residue was mixed with water, neutralized with sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. Crystallization of the residue from ethyl acetate gave S-chloro-Z-[3-(phthalimidomethyl -4H'1,2,4-triazol-4-yl]-benzophenone.

In the manner given in the preceding examples, other l-unsu-bstituted and substituted amino-6-phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepines of formulae VII or IX can be prepared. Representative compounds, thus prepared, include:

8-chloro-1- (methylamino methyl] -6- o-chlorophenyl) I 4I-I-s-triazolo [4,3-a] [1,4]benzodiazepine; 7,8-dicyano-1- (diisopropylamino) methyl] -6-(m-nitrophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepine; s-trifiuoromethyl- 1- (dimethylamino methyl] -6- (2,4-diethylphenyl) -4H-s-triazolo [4,3-a] 1,4]benzodiazepine; 8-chloro-1-[ (ethylamino methyl] -6- (o-chlorophenyl)- 4H-s-triazolo [4,3-a] 1,4]benzodiazepine; 9-isopropyl-1- (diethylamino methyl] -6- (2,4-diethoxyphenyl -4I-I-s-triazolo[4,3-a] [1,4] benzodiazepine; 10-dimethylamino-1-[ (dimethylamino methyl] -6- 3- formamidophenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepine; 8-propylsulfinyl-7-methyl-1-(morpholinomethyD-6- phenyl-4H-s-triazolo [4,3-a] 1 ,4] benzodiazepine; 7,l-dibromo-1-(pyrrolidinomethyl)-6-(o-fluorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine; 7,9-bis(methylthio) -1-(piperidinomethyl) -6-m-propylphenyl -4H-s-triazolo [4,3-a] [1,4]'benzodiazepine; S-methylsulfinyll- (4-methylpiperazino) methyl] -6-phenyl-4H-s-triazolo [4,3-a] 1,4] benzodiazepine; 9-nitro-6-fluoro-1-[ (4-methylpiperazino methyl] -6- phenyl-4H-s-triazolo [4,3 -a] 1,4] benzodiazepine; 8-chloro-1-[ (4-phenylpiperazino) methyl] -6-phenyl-4H-striazolo [4,3-a] [1,4] benzodiazepine; ,7-propionamido-1-[ dimethylamino methyl] -6- [P-Propoxyphenyl1-4H-s-triazolo [4,3-a] 1,4] benzodiazepine; 8-chloro-1- (pyrrolidinomethyl) -6-phenyl-4H-s-triazolo [4,3 -a] [1,4] benzodiazepine; 8-chloro-1-(piperidinomethyl)-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

and the like.

We claim:

1. A process for the production of 1-[ (substituted amino) methyl] 6 phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepines of formula VH:

VII

wherein R' is selected $911. the group consisting of hy- 20 drogen and alkyl of 1 to 3 carbon atoms, inclusive, wherein R is alkyl as defined above, or, together is pyrrolidino, piperidino, morpholino, 4-methylor 4- N H-/ \N N H l wherein A and B have the significance of above, with formaldehyde to obtain the corresponding 2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone of formula II N H N N CHr-OH A u wherein A and B have the significance of above;

(2) treating H with phthalimide, triphenylphosphine and diethyl azodicarboxylate for 2-36 hours at between 040 C. to obtain the corresponding 2-[3- (phthalimidomethyl)-4H-1,2,4-triazol 4 yl]benzophenone of formula III CHI-N wherein A and B have the significance of above;

21 (3) treating III with formaldehyde at 100 to 150 C.

to obtain the corresponding 2-[3-(phthalimidomethyl)-5-(hydroxymethyl) 4H-1,2,4-triazo1-4-yl]henzophenone of the formula IV:

Boom-6 N wherein A and B have the significance of above, and wherein X is chloro or bromo; treating V with an amine of the formula wherein R is alkyl defined as above, or hydrogen, wherein R" is alkyl defined as above or together is pyrrolidino, piperidino, morpholine, 4-methylor 4-phenylpiperazino, in the presence of an alkali iodide, to give the corresponding 2-[5-[(substituted amino)methyl] 3 (phthalimidomethyl)-4H-1,2,4- triazol-4-yl]benzophenone VI:

wherein R, R", A and B have the significance as defined above; and

(6) heating VI with hydrazine hydrate to give the compound of formula VII above.

2. The process of claim 1 wherein the starting material is 5-chloro-2-(4H-1,2,4-triozol-4-yl)benzophenone.

3. The process of claim 1 wherein the starting material is 2',5-dichloro-2- (4H-1,2,4-triazol-4-yl) benzophenone.

4. The process of claim 1 wherein the formaldehyde used in steps 1 and 3 is paraformaldehyde.

5. The process of claim 1 wherein in step 4 the halogenating agent is thionyl chloride and the reaction temperature is 78 to 83 C.

6. The process of claim 1 wherein the step 4 phosphorus tribromide in an organic solvent, from the group consisting of methylene chloride, chloroform, carbontetrachloride and tetrahydrofuran, is used at a temperature of 010 C. for 10-90 minutes and thereafter between 20- 40 C. for 1 to 24 hours.

7. The process of claim 1 wherein the amine in step 5 is a dialkylamine in which the alkyl group is of 1 to 3 carbon atoms, inclusive.

8. The process of claim 1 wherein the amine used in step 5 is a monoalkylamine in which the alkyl group is of 1 to 3 carbon atoms, inclusive.

9. The process of claim 1 wherein the amine in step 5 is selected from the group consisting of pyrrolidine, piperidine, morpholine, 4-methylpiperazine, and 4-phenylpiperazine.

10. A process for the production of a l-aminomethyl- 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of the formula IX wherein the rings A and B are unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, and alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino in which the carbon moiety is of 1 to 3 carbon atoms, inclusive, and dialkylamino in which the alkyl group is of 1 to 3 carbon atoms, inclusive, which comprises:

(1) heating to a temperature of -150 C. a mixture of 2 (4H 1,2,4-triazol-4-yl)benzophenone of the formula I wherein A and B have the significance of above, with formaldehyde to obtain the corresponding 2- 23 [3 (hydroxymethyl) 4H-1,2,4-triazol-4-y11benzofrom thionyl chloride and phosphorus tribromide to phenone of formula II: obtain the corresponding 2-[3-(phthalimidomethyl)- 5 (halomethyl) -4H-1,2,4-triazo1-4-yl] benzophenone of formula V:

N 5 N O Enron XCHP/ N K i A I N CH;N\ =0 A l wherein A and B have the significance of above; (2) treating II with phthalimide, triphenylphosphine V and diethyl azodicarboxylate for 2-36 hours at bewherein A and B have the significance of above; and tween 0-40 C. to obtain the corresponding 2-[3- whereinXis chloro or bromo; (phthalimidomethyl) 4H 1,2,4-triazol-4-yl1benzo- (5) treating V with ammonia gas in methanol to give phenone of the formula III: the corresponding 1-[(phthalirnidmmethyl]-6-phenyl- 4H-s-triazolo [4,3-a] [1,4]benzodiazepine of formula 0 H l VIII:

III

wherein A and B have the significance of above; (3) treating III with formaldehyde at 100 to 150 C.

to obtain the corresponding 2 [3 (phthalimidomethyl)-5-(hydroxymethyl) 4H1,2,4-triazol-4-yl] VIII benzophenone of the formula IV: wherein A and B have the significance of above; and N 0 (6) treating VIII with hydrazine hydrate in a lower HOOH u 4 alkanol of 1 to 3 carbon atoms, at reflux temperature N 0 to obtain the product of formula IX above. CH 11. The process of claim 10 wherein the lower alkanol A a is ethanol.

References Cited =0 0 UNITED STATES PATENTS 3,709,898 1/1973 Hester 260-308 R ALTON D. ROLLINS, Primary Examiner IV US. Cl. X.R. wherein A and B have the significance of above; 260-2472 A, 247.5 E, 268 TR, 293.59, 308 R; 424- (4) treating IV with a halogenating agent selected 248, 250, 267, 269.

Page 1 of 5 UNITED STATES PATENT AND TRADEMARK OFFTCE QETTHQATE or G PATENT NO. 5,842,090 DATED Octobe r 15, 97

INVENTOR( Ma rti n Gal 1 and Jackson B Hes te r, J r.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

a Column 1 l i ne 15-25; Formula X should appea r as shown below instead of as in thepatent:

i e t Column 5, l i ne 50-55: V Should read V NHE \l/ NHa O Vlll v Vlll Column 7, l ine 4, "[4,5]E2fil] should read [4,5-a][2, -l]

I l ne 56, dimethylami no should read (dimethylami no l i ne 65, "ED3Q" should read E0 Column 8, l i ne 21 "L0 should read LD Column 9, l i ne 48, "6-8 hou rs" 0 should read 2-8 hours Column 10, line #5, "ethanol" should read methanol Column 11, l ine 50, "[5-chloro-" should read [5- (chlorol ine 58, "methyl -4H" should read methyl )4H- Column 12, l l ne 11, "methyl -5" should read UNITED STATES PATENT AND TRADEMARK ohfifiE of 5 CERTIFICATE OF CORRECTION PATENT NO. 5,84

. DATED October 5, 97

lN\/ ENTOR(S) Ma rti n Gal 1 and Jackson B Hester, J r.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: 0 methyl-B- line 11, "triazolyl" should read triazol l l ne l8, 't rl azol yl should read t riazol l i ne 54, "[4,5-a[l,4]" should read [RB-1H, l ine 56, "[lfl-g" should read [1,4] l ine 75, Vll) should read (XH Column 15, line 25-55; Formula Xtl should appear as shown below a l nstead of as l n the pa tent;

Xl l. a

Page 5 of 5 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTO PATENT NO. 1 5,842,090 DATED October 15, 97

INV ENTOR(S) Ma rti n Gal 1 and Jackson B. Hes ter, J r.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: Col umn 14, l ine 5, was stl rred should read and sti rred l i he 15, (0.1 mol should read (O .1 ml l ine 54, "[5-hyd ro y should read [5- hyd ro y Col umn 15, l i ne 19, "[5-hyd ro y should read [5- hydroxy l i he 60/61, di fluorophenyl should read di fl uo rophenyl Col umn 16, l i ne 12, 4y] 1'' should read l-yl l i ne 70, "2-[5-hyd roxy should read 2-[5- (hydroxy Column 17, l i he 26, "[5-pyrshould read [5- (pyrl ine 57/58, (phthal lrni do) methyl should read (phthal imi domethyl l ine 58, t riazol e" should read t rlazol Col umn 18, l ine 51 "di hcolo ro" should read dlchloro Column 19, l i ne 39, "-6-m-" should read 6- (m- Signed and Scaled this Third Day of August 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner nj'larenrx and Trademarks 

1. A PROCESS FOR THE PRODUCTION OF 1(-(SUBSTITUTED AMINO)METHYL) -6- PHENYL-4H-S-TRIAZOLOR(4,3-A)(1,4)BENZODIAZEPINES OF FORMULA VII: 